Significant biomedical therapies are likely to result from novel biomaterials that are designed at the molecular level to offer customized control over their mechanical and biological properties. The realization of such biomaterials requires the formation of productive research relationships between the diverse communities of organic chemistry, molecular design, biology, biophysical chemistry, and materials engineering. Furthermore, the ultimate clinical implementation of new biomaterials will require consistent interactions between research scientists and the medical practitioners who can eventually translate fundamental research into the clinic. The proposed COBRE renewal application Molecular Design of Responsive Biomaterials will focus on the design of biomaterials for regeneration of liver and vocal fold tissues, and for drug-lead identification and payload delivery. A common design principle is that the macroscopic properties of these materials can be controlled in large part by the conformational properties and biological specificity of the constituent molecular building blocks, and that new chemical strategies and characterization methods will be integral to their design. Materials will be developed by evaluating of the interplay between material structure and morphology, mechanical properties, biochemical interactions, in vitro cell-material interactions, and in vivo tissue responses. These studies will ultimately generate materials systems that are optimized for their intended applications. The organization of the proposed center capitalizes on the scientific successes of our current COBRE individual subprojects, which have developed expertise and state-of-the-art core facilities for chemical, biochemical, and materials methodologies applicable to a broad spectrum of biomaterials. In addition to these scientific aims, the proposed center activities will also enhance faculty development and infrastructure development through the integration of the research team, expansion of active mentoring programs at the University of Delaware (UD), additions to the instrumentation core, establishment of new seed areas, and strategic new hires. Our research team brings together junior and early-career scientists from the UD Departments of Chemistry and Biochemistry, Materials Science and Engineering, and Chemical Engineering who will be mentored by internationally known experts in their fields. The team will also collaborate with senior investigators from UD and with clinicians from the state of Delaware's flagship research hospitals Christiana Care and A.I. duPont Hospital for Children, which will integrate biomaterials research in the state of Delaware. These efforts, coupled with new hires and projects, will establish a dynamic environment for interdisciplinary biomedical research that will increase the research competitiveness of the investigators and the team and will bring new science and potential technology to the biomaterials community.